Movement disorders are neurological disorders characterized by lack, decrease or incoordination of movement, or involuntary movements (for example, tremor, dyskinesia, chorea, ballism, dystonia, ataxia, akathisia, athetosis, tic, myoclonus etc.). Representative diseases with movement disorder include Parkinson's disease, Huntington's disease, essential tremor, tardive dyskinesia, restless legs syndrome, Tourette syndrome, progressive supranuclear palsy, spasmodic torticollis, or the like (THE MERCK INDEX 17th ed., Chapter 14; Nihon Rinsho, 1993, vol. 51, p. 2816-2822).
The neuronal assemblies responsible for the control of movement consists of the corticospinal tract that connects the cerebral cortex with the brain stem and the lower motor center of the spinal cord via medullary pyramid, the basal ganglia that directs output toward the cerebral cortex and the cerebellum which is the center of the movement-coordination. When one or more of these constituent elements are disordered, an abnormal movement pattern (movement disorder) appears. The etiology of movement disorder involves not only a neurodegenerative disease, but also a psychiatric disease, a drug effect, a mental process, or the like, where the detail of the disorder varies widely. According to the International Classification of Diseases, 10th edition (ICD-10) of WHO, the movement disorder is ranked as an “extrapyramidal disorder and abnormal behavior” or a “behavioral and emotional disorder generally developed in the infancy (childhood) and adolescence”, including a wide range of from drug-induced type and psychogenic type to those caused by neurodegeneration of the basal ganglia.
Parkinson's disease, which is a representative disease associated with movement disorder, is a neurodegenerative disease that gradually advances with age. Its characteristic symptoms are, for example, resting tremor, rigidity, akinesia, abnormal postural reflex, or the like, which are called the four major symptoms of Parkinson's disease. Pathologically, denaturation or loss of dopaminergic neuron that projects from the substantia nigra, which is a part of the extrapyramidal system, to the corpus striatum, as well as appearance of Lewy body are observed, and a remarkable decrease in the corpus striatum dopamine content is seen. The prevalence is assumed to be 100-150 people in Japan, and 100-200 people in Europe and US, per 100,000 people, the age of onset is 50-65 years old in many cases, and the incidence increases as the age grows (Nihon Rinsho, 2004, vol. 62, p. 1603-1607; Nihon Rinsho, 1997, vol. 55, p. 9-15). In addition, the disease group with the development of some of the extrapyramidal symptoms as seen in Parkinson's disease is called parkinsonism (Parkinson's syndrome), which may be caused secondarily by, for example, cerebrovascular disorder, pharmaceutical agent, poisoning, tumor, trauma, or the like, or may be caused by various neurodegenerative diseases other than Parkinson's disease. As the pharmaceutical agent that can cause parkinsonism, for example, benzamide derivatives having a dopamine receptor blocking action (for example, antipsychotic agent, antidepressant, gastrointestinal prokinetic agent etc.), antipsychotic agents of phenothiazine series and butyrophenone series, calcium antagonist, antiarrhythmic, dopamine depleting agent, or the like can be mentioned (Naika, 2004, vol. 93, p. 648-652).
The basic treatment of Parkinson's disease is an L-DOPA replacement therapy supplementing the deficient dopamine, and dopamine agonist, MAO-B (monoamine oxidation enzyme B) inhibitor, COMT (catechol-O-methyltransferase) inhibitor, anticholinergic agent, amantadine, or the like are often used in combination (Rinsho Shinkeigaku, 2002, vol. 42, p. 421-494). However, a long-term administration of L-DOPA in the L-DOPA replacement therapy (L-DOPA therapy) causes the problematic development of motor complications such as involuntary movement (e.g., dyskinesia, dystonia, or the like), wearing-off phenomenon, on-off fluctuation, or the like (THE MERCK INDEX 17th ed., Chapter 14; Nihon Rinsho, 2004, vol. 62, p. 1594-1749). Generally, once a motor complication is developed, it cannot be treated with L-DOPA or other dopamine agonist. Dyskinesia mainly includes choreiform movements, which may systemically or partially occur from the face such as in the mouth, jaw, tongue, or the like to the extremities. Dystonia frequently occurs on awakening, with equinovarus accompanying bending of the toe, and frequently with a pain. While the etiology thereof has not been elucidated sufficiently, the inability to maintain L-DOPA concentration at a certain level with the progression of dopamine neurodegeneration is considered to contribute to the motor complications (Nihon Rinsho, 2004, vol. 62, p. 1711-1715). To deal with dyskinesia, the dose of L-DOPA needs to be reduced and, when the reduction is ineffective, amantadine is added. On the other hand, for dystonia, more dopamine agonist, L-DOPA, MAO-B inhibitor and the like are added. Since these symptoms frequently appear in the advanced stage, reduction of the dose of pharmaceutical agent often aggravates the symptoms of Parkinson's disease to the extent that the activity of daily living (ADL) is affected (Rinsho Shinkeigaku, 2002, vol. 42, p. 421-494; Nihon Rinsho, 2004, vol. 62, p. 1711-1715). Moreover, side effects of nausea, vomiting, orthostatic hypotension, psychiatric symptom, or the like due to dopamine receptor stimulation by the administration of a dopaminergic pharmaceutical agent such as L-DOPA is also problematic, and a new treatment method replacing the dopaminergic pharmaceutical agents is expected.
As the triazolopyrimidine derivative having an adenosine A2A receptor antagonistic action, for example, many compounds such as [1,2,4]triazolo[1,5-c]pyrimidine derivative, [1,2,4]triazolo[1,5-a]pyrimidine derivative are known (see, for example, patent reference 1, patent reference 2, patent reference 3, patent reference 4, patent reference 5, patent reference 6, patent reference 7, patent reference 8 etc.). Moreover, it is known that a compound having an adenosine A2A receptor antagonistic action is effective for the treatment of extrapyramidal disorder, dystonia, restless legs syndrome, or the like (see patent reference 9).
patent reference 1: WO98/42711
patent reference 2: WO00/17201
patent reference 3: WO99/43678
patent reference 4: WO01/92264
patent reference 5: WO00/69464
patent reference 6: WO03/48156
patent reference 7: WO03/32996
patent reference 8: WO03/48163
patent reference 9: US Publication No. 2004/0138235